Strong anisotropic third-harmonic generation in layered violet phosphorus.

We demonstrate that layered violet phosphorus, an emerging 2D semiconductor, undergoes strong anisotropic third-harmonic generation (THG). Polarization dependence of in-plane THG presents a cruciate-flower-shaped curve. Through theoretical modeling of the in-plane THG response, done by considering crystalline symmetry of violet phosphorus, we successfully quantify four non-zero third-order nonlinear optical susceptibility tensor elements. From control experiments, the magnitude of third-order nonlinear optical susceptibility |χ3| is calculated to be about 4.0 × 10-19 m2 V-2, which is comparable to those of conventional 2D layered semiconductors. These results indicate that the layered violet phosphorus can serve as an ideal building block for nonlinear optical applications.

Double Plasma Molecular Adsorption System with Sequential Low-dose Plasma Exchange in Patients with Hepatitis B Virus-related Acute-on-chronic Liver Failure: A Prospective Study.

Background and Aims: To investigate the safety and efficacy of double plasma molecular adsorption system (DPMAS) with sequential low-dose plasma exchange (LPE) in treating early hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). Methods: Clinical data of patients with HBV-ACLF were prospectively collected, including patients in a DPMAS with sequential LPE (DPMAS+LPE) group and those in a standard medical treatment (SMT) group. The primary endpoint was death or liver transplantation (LT) at 12 weeks of follow-up. Propensity-score matching was performed to control the effects of confounding factors on prognosis between the two groups. Results: After 2 weeks, total bilirubin, alanine aminotransferase, blood urea nitrogen levels, and Chinese Group on the Study of Severe Hepatitis B score, were significantly lower in the DPMAS+LPE group than those in the SMT group (p<0.05). After 4 weeks, laboratory parameters of the two groups were similar. The cumulative survival rate of the DPMAS+LPE group was significantly higher than that of the SMT group at 4 weeks (97.9% vs. 85.4%, p=0.027), but not at 12 weeks (85.4% vs. 83.3%, p=0.687). Cytokine levels were significantly lower in 12-week survival group than in the death-or-LT group (p<0.05). Functional enrichment analysis showed that downregulated cytokines were mainly involved in positive regulation of proliferation and activation of lymphocytes and monocytes, regulation of immune effect response, regulation of endotoxin response, and glial cell proliferation. Conclusion: DPMAS+LPE significantly improved the 4-week cumulative survival rate, and ameliorated the inflammatory response in patients. DPMAS+LPE may be a promising modality for patients with early HBV-ACLF.

Safety and efficacy of double plasma molecular adsorption system with sequential low-volume plasma exchange in intermediate-stage hepatitis B virus-related acute-on-chronic liver failure.

Current evidence suggests that the mortality rate of intermediate-stage hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) remains high. We aimed to investigate the safety and efficacy of double plasma molecular adsorption system (DPMAS) with sequential low-volume plasma exchange (LPE) treatment in intermediate-stage HBV-related ACLF. This prospective study recruited intermediate-stage HBV-related ACLF patients and was registered on ClinicalTrials.gov (NCT04597164). Eligible patients were randomly divided into a trial group and a control group. Patients in both groups received comprehensive medical treatment. Patients in the trial group further received DPMAS with sequential LPE. Data were recorded from baseline to Week 12. Fifty patients with intermediate-stage HBV-related ACLF were included in this study. The incidence of bleeding events and allergic reactions in the trial group was 12% and 4%, respectively, with no other treatment-related adverse events. The levels of total bilirubin and prothrombin time-international normalized ratio, and model for end-stage liver disease scores after each session of DPMAS with sequential LPE were significantly lower than those before treatment (all p < 0.05). The 12-week cumulative liver transplantation-free survival rates in the trial and control groups were 52% and 24%, respectively (p = 0.041). The 12-week cumulative overall survival rates in the trial and control groups were 64% and 36%, respectively (p = 0.048). The Kaplan-Meier survival analysis revealed significant differences in liver transplantation-free survival (p = 0.047) and overall survival (p = 0.038) between the trial and control groups. Cox regression analysis indicated that blood urea nitrogen (p = 0.038), DPMAS with sequential LPE (p = 0.048), and Chinese Group on the Study of Severe Hepatitis B-ACLF II score (p < 0.001) were significant risk factors for mortality. DPMAS with sequential LPE treatment is safe and effective for patients with intermediate-stage HBV-related ACLF.

Human liver tissue transcriptomics revealed immunometabolic disturbances and related biomarkers in hepatitis B virus-related acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a major cause of liver-related death worldwide, but its key pathological features remain incompletely defined. This study aimed to reveal the molecular basis of hepatitis B virus-related ACLF (HBV-ACLF) by transcriptome sequencing of human liver tissue. A total of 18 human liver tissues from patients with different stages of HBV-related disease were collected for RNA sequencing, and liver tissues from patients and mouse models with ACLF were used for subsequent validation. Specifically, 6,853 differentially expressed genes (DEGs) and 5,038 differentially expressed transcripts were identified in patients with ACLF compared to patients with chronic hepatitis B (CHB) and normal controls (NCs). Investigation of functional by KEGG pathway enrichment analysis revealed prominent immune and metabolic dysregulation at the ACLF stage. We found that the key genes FGF19, ADCY8 and KRT17, which are related to immunometabolic disturbances, were significantly upregulated in the progression of ACLF. The three key genes were validated in human and mouse samples, indicating their prognostic and therapeutic potential in ACLF. In summary, our work reveals that immunometabolic disorder is involved in HBV-ACLF pathogenesis and indicates that FGF19, ADCY8 and KRT17 may be sensitive biomarkers for HBV-related ACLF.

The relationship between zinc deficiency and infectious complications in patients with hepatitis B virus-related acute-on-chronic liver failure.

Background: The prevalence of zinc deficiency is high in patients with chronic liver disease, but few studies have hitherto explored the relationship between the serum zinc level and hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). This study aimed to assess the association between zinc deficiency and infectious complications, and model for end-stage liver disease (MELD) score in patients with HBV-related ACLF. Methods: Patients with HBV-related ACLF from the Department of Infectious Diseases of the Third Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between January 2019 and December 2019 were retrospectively analysed in this study. Their demographic, clinical, and laboratory data were retrieved from the hospital information system and analysed. The Student's t-test was used for normally distributed continuous variables between two groups and the Chi-square test was used for categorical data. Univariate and multivariate logistic regression analyses were applied to identify independent parameters. Results: A total of 284 patients were included in this study, including 205 liver cirrhosis and 79 non-cirrhosis patients. The proportion of patients with zinc deficiency was the highest (84.5%), followed by subclinical zinc deficiency (14.1%) and normal zinc level (1.4%). Patients in the zinc deficiency group had a higher MELD score than the subclinical zinc deficiency or normal zinc group (P = 0.021). Age, total bilirubin, and serum zinc level were independent factors for infection (Ps < 0.05). The serum zinc level in patients without complications at admission was significantly higher than that in patients with complications (P = 0.004). Moreover, the serum zinc level in patients with prothrombin time activity (PTA) of <20% was significantly lower than that in patients with 20% ≤ PTA < 30% (P = 0.007) and that in patients with 30% ≤ PTA < 40% (P < 0.001). Conclusions: Zinc deficiency is common in patients with HBV-related ACLF. Zinc deficiency is closely associated with infectious complications and MELD score in patients with HBV-related ACLF.

Label-Free Sensing of Biomolecular Adsorption and Desorption Dynamics by Interfacial Second Harmonic Generation.

Observing interfacial molecular adsorption and desorption dynamics in a label-free manner is fundamentally important for understanding spatiotemporal transports of matter and energy across interfaces. Here, we report a label-free real-time sensing technique utilizing strong optical second harmonic generation of monolayer 2D semiconductors. BSA molecule adsorption and desorption dynamics on the surface of monolayer MoS2 in liquid environments have been all-optically observed through time-resolved second harmonic generation (SHG) measurements. The proposed SHG detection scheme is not only interface specific but also expected to be widely applicable, which, in principle, undertakes a nanometer-scale spatial resolution across interfaces.

High Expression of POGK Predicts Poor Prognosis in Patients with Hepatocellular Carcinoma.

OBJECTIVE: Kruppel-associated box (KRAB) proteins reportedly play a dual role in neoplastic transformation. At present, little is known about the function of the proteins encoded by the human pogo transposable element derived with KRAB domain (POGK) gene. Herein, we evaluated the prognostic significance of POGK expression in patients with hepatocellular carcinoma (HCC). METHODS: The data of HCC patients was downloaded from The Cancer Genome Atlas (TCGA) database. To determine the relationship between POGK and clinical features, logistic regression was applied. Cox regression and Kaplan-Meier analyses were used to evaluate the correlation between POGK and survival rates. Gene ontology (GO) analysis and Gene set enrichment analysis (GSEA) were conducted to identify the enriched pathways and functions associated with POGK. RESULTS: A total of 374 HCC patients were identified in TCGA. POGK was significantly upregulated in HCC and correlated with tumor status (p = 0.036), race (p = 0.025), weight (p = 0.002), body mass index (p = 0.033), histologic grade (p < 0.001), and alpha-fetoprotein (p < 0.001). High POGK expression in HCC patients correlated with a poor outcome in terms of overall survival (p = 0.0018), progression-free survival (p = 0.0087), relapse-free survival (p = 0.045), and disease-specific survival (p = 0.014), according to Kaplan-Meier analysis. Receiver operating characteristic curve analysis showed that the area under the curve of POGK expression for HCC diagnosis was 0.891. GSEA showed that high POGK expression might activate mitotic prometaphase, kinesins, homologous DNA pairing and strand exchange, MET activates PTK2 signaling pathway, G1 to S cell cycle control, Aurora B pathway, ncRNAs involved in WNT signaling pathway, hepatitis C, and ncRNAs involved in the STAT3 signaling pathway. POGK expression correlated with the abundance of adaptive and innate immunocytes in HCC. CONCLUSION: High expression of POGK has high diagnostic and prognostic values in patients with HCC. Moreover, POGK expression is correlated with immune infiltration in HCC.

NTCP Deficiency Affects the Levels of Circulating Bile Acids and Induces Osteoporosis.

Background: The p.Ser267Phe mutation in the SLC10A1 gene can cause NTCP deficiency. However, the full clinical presentation of p.Ser267Phe homozygous individuals and its long-term consequences remain unclear. Hence, in the present study, we characterized the phenotypic characteristics of NTCP deficiency and evaluated its long-term prognosis. Methods: Ten NTCP p.Ser267Phe homozygous individuals were recruited and a comprehensive medical evaluation with a 5-year follow-up observation was performed. The phenotypic characteristics of NTCP deficiency were also demonstrated using an NTCP-global knockout mouse model. Results: During the 5-year follow-up observation of 10 NTCP p.Ser267Phe homozygous adults, we found that the most common phenotypic features of NTCP deficiency in adults were hypercholanemia, vitamin D deficiency, bone loss, and gallbladder abnormalities. The profile of bile acids (BAs) in the serum was significantly altered in these individuals and marked by both elevated proportion and concentration of primary and conjugated BAs. Moreover, the NTCP deficiency led to increased levels of serum BAs, decreased levels of vitamin D, and aggravated the osteoporotic phenotype induced by estrogen withdrawal in mice. Conclusions: Both mice and humans with NTCP deficiency presented hypercholanemia and were more prone to vitamin D deficiency and aggravated osteoporotic phenotype. Therefore, we recommend monitoring the levels of BAs and vitamin D, bone density, and abdominal ultrasounds in individuals with NTCP deficiency.

Prognostic value of decline in model for end-stage liver disease score and hepatic encephalopathy in hepatitis B-related acute-on-chronic liver failure patients treated with plasma exchange.

OBJECTIVE: To investigate the prognostic value of Model for End-Stage Liver Disease (MELD) score and Hepatic Encephalopathy (HE) for short-term prognosis of Hepatitis B virus-related Acute-on-Chronic Liver Failure (HBV-ACLF) patients treated with plasma exchange (PE). METHODS: A total of 108 patients with HBV-ACLF treated with PE were retrospectively enrolled between January 2014 to December 2020. Based on survival at 28 days, patients were divided into survival (N = 87) and death groups (N = 21). Clinical data and laboratory indicators were analyzed. RESULTS: Compared with the survival group, the death group was associated with higher ACLF grade and incidence of HE. The levels of total bilirubin, prothrombin time, creatinine, blood urea nitrogen, MELD score, and Chinese Group on the Study of Severe Hepatitis B-ACLF II (COSSH II) score were significantly higher in the death group than in the survival group (p < .05). Grade 1 ACLF and the MELD score after PE treatment at one week were independent risk factors for 28-day liver transplantation-free mortality (OR = 0.062, 95%CI: 0.005-0.768; OR = 1.328, 95%CI: 1.153-1.531). A MELD score at one week of at least 25.5 was associated with a poor short-term prognosis. Of note, HE was a strong independent risk factor for a decline in MELD score at one week. (OR = 11.815, 95%CI: 3.187-43.796, p < 0.001). CONCLUSION: We found patients with HE at admission and MELD score of at least 25.5 at one week after PE treatment had a poor short-term prognosis and should prompt preparation for liver transplantation. Trial Registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04231565). Registered 13 May 2020.

Long-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure: a retrospective study.

BACKGROUND: The long-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is not well characterised. We assessed long-term outcomes and the associated risk factors of HBV-ACLF patients in southern China. METHODS: We retrospectively analysed clinical data, adverse events, and clinical endpoint events of HBV-ACLF patients treated at our department between January 2014 and December 2018. RESULTS: A total of 616 (52.3%) patients with cirrhosis and 561 (47.7%) patients without cirrhosis were included. In 973 (83%) patients, the disease was associated only with HBV, while 204 (17%) patients had two or more aetiological factors. The proportion of patients receiving antiviral treatment for HBV was low (20.3%). Further analyses indicated that patients without cirrhosis had a significantly lower 90-day liver transplantation-free mortality and higher 5-year survival rate than those with cirrhosis (59.5% vs. 27.6%; 62% vs. 36%; P < 0.05). Remarkably, self-withdrawal of nucleos(t)ide analog (NA) was an independent risk factor for short-term prognosis. Age, cirrhosis at admission, and platelet level were closely related to long-term prognosis of HBV-ACLF patients. CONCLUSION: The proportion of HBV-ACLF patients receiving antiviral treatment is very low in south China. Cirrhosis at admission has a significant effect on both short-term and long-term prognosis. No significant improvement in the short-term prognosis of HBV-ACLF patients was observed compared with previous studies. More comprehensive access to antiviral treatment and long-term surveillance of HBV patients are key imperatives to reduce the incidence of HBV-ACLF and improve the prognosis. Trial Registration The trial was registered at ClinicalTrials.gov (CT.gov identifier: NCT04231565) on May 13, 2020: https://register. CLINICALTRIALS: gov/prs/app/action/SelectProtocol?sid=S0009OZY&selectaction=Edit&uid=U00036P1&ts=2&cx=27seqt.

Cost-effectiveness analysis of first-line treatment for chronic hepatitis B in China.

OBJECTIVES: Hepatitis B virus infection is an important public health problem. We analysed the cost-effectiveness of the first-line therapies, including nucleotide analogues (namely tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF) and entecavir) and pegylated interferon (Peg-IFN) for patients with chronic hepatitis B (CHB) in China. METHODS: A Markov model describing CHB disease progression was constructed to compare the cost-effectiveness of the first-line therapies, considering both satisfactory (HBeAg seroconversion) and optimal (HBsAg seroclearance) treatment goals. We examined the main outcomes, including cumulative lifetime cost per patient, incremental quality-adjusted life years (QALYs), incremental cost-effectiveness ratio and net monetary benefit. Uncertainty analysis was conducted to identify key influential parameters. RESULTS: Compared with the baseline strategy, Peg-IFN had the highest QALY gain for HBeAg-positive (HBeAg+) CHB patients achieving a satisfactory goal and an optimal goal (3.19 and 6.32 respectively), and TDF was the most cost-effective therapy for HBeAg-negative CHB patients ($1418/QALY) achieving a satisfactory goal. Among nucleotide analogues, TAF was the most-effective strategy and had higher acceptability to achieve an optimal goal in the Eastern region of China (under 1 x GDP per capita threshold). CONCLUSIONS: Among nucleotide analogues, TDF was the most cost-effective treatment in China for CHB patients to achieve satisfactory and optimal treatment goals, whereas TAF was cost-effective and more effective in the wealthier region. Peg-IFN was most cost-effective among HBeAg+ CHB patients to achieve both goals, with better clinical outcomes. Our findings also indicate the importance of regular monitoring during and after CHB treatment, and could inform treatment strategies in China and other countries.

Efficacy and safety of combination treatment of double plasma molecular adsorption system and low volume plasma exchange for patients with hepatitis B virus related acute-on-chronic liver failure: a multicentre randomised controlled clinical trial.

INTRODUCTION: Hepatitis B virus (HBV) related acute-on-chronic liver failure (ACLF) is still a common type of liver failure in China. Therefore, we conduct this multicentre, non-blinded, randomised controlled clinical trial to investigate the efficacy and safety of combination treatment of double plasma molecular adsorption system (DPMAS) and low volume plasma exchange (PE) for patients with HBV related ACLF. METHODS AND ANALYSIS: A total of 200 patients with HBV related ACLF in the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou Eighth People's Hospital, Nanfang Hospital of Southern Medical University, The Third People's Hospital of Shenzhen, Xiangya Hospital of Central South University and The First Affiliated Hospital of Anhui Medical University, will be recruited into this trial. Eligible patients will undergo randomisation at a 1:1 ratio to two arms: the control group and the trial group. Patients in control group will receive comprehensive internal medical treatment. Patients in trial group will receive treatment of DPMAS and sequential low volume PE for three times, and comprehensive internal medical treatment. Clinical safety will be assessed by the analysis of adverse events (AEs) and laboratory tests. The primary efficacy outcome will be the incidence of unfavored events including death, liver transplantation and treatment abandonment. The secondary efficacy outcome will be the model for end-stage liver disease score variation. All evaluations will be performed at baseline, and 4, 8, 12, 24, 36, 48 weeks after enrolment. All AEs will be reported as soon as they are noted during the entire study procedure. ETHICS AND DISSEMINATION: This study was approved by Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (approval no. (2020)02-173-01). The results and conclusions of this clinical trial will be published at academic conferences or in journals. TRIAL REGISTRATION NUMBER: NCT04597164.

NLRX1 can counteract innate immune response induced by an external stimulus favoring HBV infection by competitive inhibition of MAVS-RLRs signaling in HepG2-NTCP cells.

INTRODUCTION: This study is aimed at the determination of the effect of the immune-regulatory factor NLRX1 on the antiviral activity of hepatocytes against an external stimuli favoring hepatitis B virus infection, and to explore its mechanism of action. METHODS: A HepG2-NTCP model was established using the LV003 lentivirus. Cells were transfected using an overexpression vector and NLRX1 siRNA to achieve overexpression and interference of NLRX1 expression (OV-NLRX1, si-NLRX1). Levels of HBsAg and HBcAg were determined using Western blotting analysis and immunohistochemical analysis. The levels of hepatitis B virus DNA and hepatitis B virus cccDNA were determined by real-time quantitative polymerase chain reaction. The expression and transcriptional activity of IFN-α, IFN-ß, and IL-6 were measured using real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and promoter-luciferase reporter plasmids. Co-immunoprecipitation was used to determine the effect of NLRX1 on the interaction between MAVS and RIG-1. Western blotting was used to obtain the phosphorylation of essential proteins in the MAVS-RLRs signaling pathways. RESULTS: NLRX1 promoted HepG2-NTCP cell hepatitis B virus infection. Compared to the control group, the levels of HBsAg, HBcAg, hepatitis B virus cccDNA, and hepatitis B virus DNA increased in the OV-NLRX1 group and decreased in the si-NLRX1. Co-immunoprecipitation results showed that NLRX1 competitively inhibited the interaction between MAVS and RIG-1, and inhibited the phosphorylation of p65, IRF3, and IRF7. Additionally, NLRX1 reduced the transcription activity and expression levels of the final products: IFN-α, IFN-ß, and IL-6. CONCLUSIONS: NLRX1 can counteract innate immune response induced by an external stimuli favoring hepatitis B virus infection by competitive inhibition of MAVS-RLRs signaling in HepG2-NTCP cells. Inhibition of the MAVS-RLR-mediated signaling pathways leads to a decline in the expression levels of I-IFN and IL-6.

The 96-week clinical outcomes after cessation of nucleos(t)ide analog treatment in chronic hepatitis B patients.

BACKGROUND: Chronic hepatitis B (CHB) patients have a high virological relapse rate after cessation of nucleos(t)ide analog (NA) treatment, but the clinical outcome remains unclear. This study aimed to investigate the 96-week clinical outcomes and the risk factors for relapse in CHB after cessation of NAs. METHODS: This study was a prospective trial; 74 eligible patients were enrolled. The patients underwent NA cessation and follow-up according to the 2012 Asian Pacific Association for the Study of the Liver Guideline. Symptoms, biochemical (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, urea nitrogen, creatinine), virological data (hepatitis B surface antigen [HBsAg], hepatitis B e antigen [HBeAg], hepatitis B e antibody [HBeAb], hepatitis B virus [HBV] DNA levels), and color Doppler ultrasound examination results were recorded and analysed. RESULTS: After NA cessation, 19 cases were HBsAg-negative without relapse during the 96-week follow-up. Of the 55 cases of HBsAg-positive after cessation, four types of clinical outcomes were observed. Twelve patients had no relapse during the 96-week follow-up (type A, 21.8%), 7 patients underwent virological relapses but spontaneously had a non-virological relapse (type B, 12.7%), 10 patients maintained virological relapse (type C, 18.2%), and 26 patients turned to clinical relapse, received NA retreatment, and achieved ALT normalization and negative conversion of HBV DNA within 12 months (type D, 47.3%). The 2-year overall cumulative rates of virological and clinical relapses were 58.1% and 24.3%, respectively. Independent factors associated with virological relapse were duration of negative HBV DNA, EOT (end of treatment) HBsAg, and original status of HBeAg. The EOT HBsAg was also an independent factor for clinical relapse. CONCLUSIONS: There are four types of clinical outcomes in patients with CHB after cessation of NA treatment. Further research is needed to explore the mechanism of different clinical outcomes. The EOT HBsAg level is an independent factor associated with both virological and clinical relapse.

Serum from Acute-on-chronic Liver Failure Patients May Affect Mesenchymal Stem Cells Transplantation by Impairing the Immunosuppressive Function of Cells.

BACKGROUND AND AIMS: The safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of acute-on-chronic liver failure (ACLF) have been validated. However, the impact of the pathological ACLF microenvironment on MSCs is less well understood. This study was designed to explore the changes in the functional properties of MSCs exposed to ACLF serum. METHODS: MSCs were cultured in the presence of 10%, 30% and 50% serum concentrations from ACLF patients and healthy volunteers. Then, the cell morphology, phenotype, apoptosis and proliferation of MSCs were evaluated, including the immunosuppressive effects. Subsequently, mRNA sequencing analysis was used to identify the molecules and pathways involved in MSC functional changes in the context of ACLF. RESULTS: In the presence of ACLF serum, MSC morphology significantly changed but phenotype did not. Besides, MSC proliferation activity was weakened, while the apoptosis rate was lightly increased. Most importantly, the immunosuppressive function of MSCs was enhanced in a low-concentration serum environment but transformed into a proinflammatory response in a high-concentration serum environment. RNA sequencing indicated that 10% serum concentration from ACLF patients mediated the PI3K-Akt pathway to enhance the anti-inflammatory effect of MSCs, while the 50% serum concentration from ACLF patients promoted the conversion of MSCs into a proinflammatory function by affecting the cell cycle. CONCLUSIONS: The 50% ACLF serum concentration is more similar to the environment in the human body, which means that direct peripheral blood intravenous infusion of MSCs may reduce the effect of transplantation. Combining treatments of plasma exchange to reduce harmful substances in serum may promote MSCs to exert a stronger anti-inflammatory effect.

Association between the nasopharyngeal microbiome and metabolome in patients with COVID-19.

SARS-CoV-2, the causative agent for COVID-19, infect human mainly via respiratory tract, which is heavily inhabited by local microbiota. However, the interaction between SARS-CoV-2 and nasopharyngeal microbiota, and the association with metabolome has not been well characterized. Here, metabolomic analysis of blood, urine, and nasopharyngeal swabs from a group of COVID-19 and non-COVID-19 patients, and metagenomic analysis of pharyngeal samples were used to identify the key features of COVID-19. Results showed lactic acid, l-proline, and chlorogenic acid methyl ester (CME) were significantly reduced in the sera of COVID-19 patients compared with non-COVID-19 ones. Nasopharyngeal commensal bacteria including Gemella morbillorum, Gemella haemolysans and Leptotrichia hofstadii were notably depleted in the pharynges of COVID-19 patients, while Prevotella histicola, Streptococcus sanguinis, and Veillonella dispar were relatively increased. The abundance of G. haemolysans and L. hofstadii were significantly positively associated with serum CME, which might be an anti-SARS-CoV-2 bacterial metabolite. This study provides important information to explore the linkage between nasopharyngeal microbiota and disease susceptibility. The findings were based on a very limited number of patients enrolled in this study; a larger size of cohort will be appreciated for further investigation.

The NTCP p.Ser267Phe Variant Is Associated With a Faster Anti-HBV Effect on First-Line Nucleos(t)ide Analog Treatment.

Sodium taurocholate cotransporting polypeptide (NTCP) acts as a cellular receptor for the hepatitis B virus infection of host hepatocytes. Previously, many studies confirmed that the NTCP p.Ser267Phe variant was a protective factor against HBV-related disease progression. We therefore designed this study to investigate whether the NTCP p.Ser267Phe variant exerts an additive anti-HBV effect in chronic hepatitis B (CHB) patients on mainstream NAs treatment. After propensity score matching (PSM), a total of 136 CHB patients were included, among whom 68 were heterozygous carriers and 68 were wild-type controls. Proportions of primary nonresponse, partial virological response, virological breakthrough and hepatitis B reactivation and the HBV DNA clearance rate at each time point were compared using the chi-square test. Kaplan-Meier analysis and matched t-tests were also performed to estimate the speed of viral clearance and serum HBV DNA reduction, respectively. The proportion of primary nonresponse was significantly lower in heterozygous carriers than in wild-type controls (p < 0.001), especially in patients using entecavir (p = 0.013). Specifically, heterozygous carriers achieved HBV DNA clearance faster than wild-type controls (log-rank p = 0.0198). HBV DNA levels were reduced more in heterozygous carriers after 12 weeks (p < 0.001) and 24 weeks (p = 0.006) of treatment, especially among patients using ETV. Here, our study demonstrated that heterozygous mutations in rs2296651 enhanced the antiviral response of first-line NAs and helped to explore the possibility of combining NAs and NTCP blockers for a better anti-HBV effect.

TMEM2 binds to CSNK2A3 to inhibit HBV infection via activation of the JAK/STAT pathway.

To investigate mechanisms that TMEM2 activation inhibits hepatitis B virus (HBV) infection in hepatocarcinoma (HCC) cells, co-immunoprecipitation (Co-IP) and mass spectrometry were used in screening interacting proteins for TMEM2. Levels of casein kinase 2 subunit α3 (CSNK2A3) in HCC cells were found to be inhibited or overexpressed using siRNAs and pcDNA3.1-CSNK2A3, respectively. Effect of CSNK2A3 expression on cell proliferation was analyzed using MTS, while its effect on HBV infection was measured using ddPCR and IHC. Western blotting and JAK inhibitor ruxolitinib were also used to determine whether TMEM2-regulated CSNK2A3 expression and HBV infection were affected by JAK-STAT signaling. Co-IP and mass spectrometry results showed that CSNK2A3 interacts with TMEM2. Moreover, overexpression of CSNK2A3 significantly inhibited cell proliferation, while inhibition of CSNK2A3 promoted proliferation of HCC cells. In addition, overexpression of CSNK2A3 was observed to significantly enhance HBV infection, while siRNA knockdown of CSNK2A3 inhibited HBV infection. Notably, effect of CSNK2A3 overexpression on HBV infection was suppressed by TMEM2 overexpression. Further mechanistic analyses have revealed that TMEM2 could antagonize the effects of CSNK2A3 on cell proliferation and HBV infection via JAK-STAT pathway activation. In conclusion, TMEM2 has been determined to bind to CSNK2A3 to inhibit HBV infection via activation of the JAK-STAT pathway.

The 48-week safety and therapeutic effects of tenofovir alafenamide in hbv-related acute-on-chronic liver failure: A prospective cohort study.

Tenofovir alafenamide (TAF) has been available in China for a short time, little is known about its safety and efficacy in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (HBV-ACLF). We conducted this study to further verify the safety and efficacy of TAF in these patients. Eighty-eight eligible subjects were included and divided into three groups: TAF group, TDF group and ETV group. Clinical and laboratory test results were collected and the survival status, virus suppression status and liver and renal function improvement were observed during follow-up. No drug-related adverse events were observed within a 48-week observation period. At week 48, the survival rates of the three groups were 56.5%, 78.3% and 59.5% (p = 0.262). HBV DNA undetectable rates were similar (80.0% vs.75.0% vs.84.6%, respectively, p = 0.863). Liver function improved in all the three groups over time. Compared with the other two groups, patients in the TAF group had a greater decrease in serum creatinine (CR) and an increase in estimated glomerular filtration rate (eGFR), especially at week 12. At week 48, the median changes of CR were -0.7 (IQR -3.0, 13.0) vs. 15.0 (IQR -3.0, 21.0) vs. 5.0 (IQR -9.0, 14.0), respectively (p = 0.334), while the median changes of eGFR were -2.12 (IQR -13.87, 1.44) vs. -10.43 (IQR -20.21, 3.18) vs. -5.31 (IQR -14.72, 5.44) ml/min/1.73 m2 , respectively (p = 0.592). In this real-world clinical study, TAF is as effective as TDF and ETV, and may be more beneficial in protecting renal function in the early stages of antiviral therapy.

SnSe2 realizes soliton rain and harmonic soliton molecules in erbium-doped fiber lasers.

Two-dimensional layered metal chalcogenides (LMCs) are widely used in battery anode materials, energy conversion, and semiconductor devices, because of their high energy storage characteristics, high thermoelectric characteristics, and large electron mobility. SnSe2 as a kind of LMC has strong nonlinear optical characteristics. However, its research on dissipative system dynamics as a saturable absorber has not been studied. In this work, we obtained SnSe2 nanosheets using lithium ion intercalation and we reported a passively mode-locked fiber laser with SnSe2 as a saturable absorber to achieve the dissipative soliton in a dissipative system. Due to the high third-order nonlinearity of SnSe2, the evolution of square wave pulses from 2 to 16 ns was obtained in a fiber ring cavity. Through adjusting the polarization state, the evolution phenomenon of soliton rain, the soliton rain phenomenon with a spectrum of dual-wavelengths, and a bound state harmonic phenomenon with a frequency of 313 MHz were obtained. Therefore, the strong nonlinear fiber laser based on SnSe2 provides a good platform for study the pulsation, explosion, rainfall and other phenomena.